Statin therapy for cardiovascular disease prevention is a mainstay of treatment. However, emerging data suggest that statin initiation is also accompanied by a modest increase in risk of clinical diabetes. Six large randomized clinical trials have collected data on diabetes outcomes and demonstrate a modest but highly significant effect (summary relative risk: 1.13; 95% CI 1.03-1.24, p=0.007) that does not appear to be drug or dose specific, nor easily predicted on the basis of traditional risk factors. The mechanisms of statin-induced diabetes are currently unknown, but the pleiotropic effects of these agents suggest multiple pathways should be considered. The JUPITER trial in which 17,802 apparently healthy non-diabetic men and women were initiated on rosuvastatin (20 mg per day) or placebo offers a unique opportunity in which to examine this issue. The relative risk of diabetes associated with random allocation to rosuvastatin in JUPITER was 1.26 (1.05-1.51; p=0.02). Employing two complementary prospective approaches, we propose to comprehensively evaluate a series of biomarkers reflecting twelve plausible mechanisms of statin-induced diabetes. These will include biomarkers of: 1) insulin resistance, 2) 2-cell function, 3) adipocyte signaling, 4) hepatic dysfunction/iron overload, 5) lipid metabolism, 6) growth factor activity, 7) apoptosis, 8) inflammation, 9) endothelial dysfunction, 10) branched chain amino acid metabolism, 11) natriuretic peptide activity and 12) osteo-endocrine regulation. In Phase One of this research program, we will evaluate statin effects on these pathways by measuring change in biomarker levels from baseline to 1-year in a representative sample of JUPITER participants (400 allocated to rosuvastatin and 400 allocated to placebo). In Phase Two, utilizing a prospective case-cohort approach, we will also assess biomarker relationships with clinical type 2 diabetes. Case subjects (n=540) will be JUPITER participants who were free of clinical or biochemical (fasting plasma glucose < 126 mg/dL) diabetes at baseline who develop clinical or biochemical (fasting plasma glucose > 126 mg/dL) diabetes during follow-up. The subcohort (n=2,000) will be a randomly selected sample of the parent JUPITER population. Biomarkers will be assessed in pathophysiologic groups based upon plausible biologic pathways as well as data generated in Phase One. Data on usual demographic, clinical and behavioral risk factors will be used to evaluate potential confounding and effect modification. These analyses will take advantage of a unique blood bank from a cohort of 17,802 primary prevention patients that is ethnically diverse (>5000 non-Caucasian participants) and includes 6,801 women and will thus provide a cost-efficient method to evaluate statin therapy and diabetes risk in an unprecedented manner. If funded, the findings generated from this application should additionally provide a method for identifying those at greatest risk of type 2 diabetes, an issue that is likely to increase in importance as indications for statin therapy continue to broaden. PUBLIC HEALTH RELEVANCE: The cardiovascular benefit of HMG-CoA reductace inhibitors (statins) is unequivocal. However, recently published data deriving from several large randomized clinical trials of statin initiation for cardiovascular disease prevention have raised concern regarding a modest increase in risk of type 2 diabetes. This effect does not appear to be drug or dose specific, nor easily predicted on the basis of traditional risk factors. Findings from this prospective evaluation of statin-induced diabetes within the Justification for the Use of Statins in Prevention: and Intervention trial Evaluating Rosuvastatin (JUPITER) trial will clarify the impact of statins on multiple metabolic pathways implicated in diabetogenesis and will offer a method of identifying individuals at greatest risk for drug-associated diabetes, an issue likely to take on increasing importance as indications for statin therapy expand.